Infections of the maternally transmitted intracellular bacteria Wolbachia are widespread in nature, found in most insects and in parasitic worms. Many insects that harbor these bacteria are the vectors of devastating human infectious diseases. The biology at the interface between Wolbachia and their hosts offers novel strategies for the control of disease vectors. Fruit fly Wolbachia strains can invade and sustain themselves in mosquito populations, reduce adult lifespan, affect mosquito reproduction and inhibit the ability of several pathogens to infect mosquitoes, including Dengue, Chikungunya, West Nile Virus, and both chicken and human plasmodium. Nevertheless, very little is known about the mechanistic basis for Wolbachia-insect host interactions, limiting the capability of fully exploitig Wolbachia's biology towards control efforts. The goal of this application is to investigate the cellular and molecular mechanisms of Wolbachia manipulation of insect reproduction. Wolbachia often alter their host's reproductive ability; yet, very little is known about how this i achieved. We identified the developmental processes that Wolbachia interfere with to increase the levels of host egg production. Wolbachia maternal transmission is enhanced by bacterial inhibition of germ cells death during egg production. Furthermore, Wolbachia can upregulate the rate of proliferation of the germline stem cells, further increasing transmission of bacteria via te egg. To dissect the cellular and molecular mechanisms of these novel host manipulations, we will: 1. Determine the effects of different Wolbachia strains in germline programmed cell death in D. melanogaster, Culex pipiens and Aedes aegypti. 2. Investigate the effect of infection on stem cell division with different Wolbachia strain-host species. 3. Determine Wolbachia-induced differences in the transcriptional profile that affect stem cell proliferation. Our studies of Wolbachia interaction with their hosts at the cellular and molecular level will yield valuable new information on basic biology of symbiotic interactions during oogenesis. This fundamental knowledge provide the foundation for the development of new cell biological and Wolbachia based strategies for disease control. Furthermore, Wolbachia interaction with stem cell niches and manipulation of stem cell proliferation will expand our basic understanding of the properties of stem cell niches and how they control stem cell proliferation.